Pharmacokinetic Characteristics of a Nifedipine and Lidocaine Fixed Combination in the Form of Rectal Cream: Two Decades Data Analysis
DOI:
https://doi.org/10.20535/ibb.2021.5.1.227361Keywords:
nifedipine, lidocaine, fixed combination, pharmacokinetic characteristicsAbstract
The creation of medicines' fixed combinations from compounds with complementary effects is one of the most popular directions in modern pharmacology and pharmaceutics. In case of nifedipine and lidocaine fixed combination such approach is quite obvious. The present review article is devoted to the analysis of clinical and non-clinical studies results on the assessment of the pharmacokinetic characteristics of these medicines. Although the oral route is the most convenient for drug administration, there are a number of circumstances where this is not possible from either a clinical or pharmaceutical perspective. In these cases, the rectal route may represent a practical alternative and can be used to administer drugs for both local and systemic actions. Research data of last decades suggested that nifedipine, a calcium channel blocker, could be effective in reducing anal resting pressure and in healing chronic anal fissure and acute thrombosed hemorrhoids. Another component of fixed combination lidocaine is a local anesthetic usually used to relieve pain of anal fissures and symptomatic hemorrhoids. In combinations lidocaine and nifedipine have complementary actions. Analysis of all available studies (during last 2 decades) which were aimed to investigate pharmacokinetic characteristics of a nifedipine and lidocaine fixed combination in the form of rectal cream showed that following topical application, the active ingredients nifedipine and lidocaine are absorbed into the bloodstream in only small quantities that have no major implications for the safety of the product, and systemic absorption, if any, was incomparably lower than absorption following per os administration of the two active ingredients.
References
Hua S. Physiological and Pharmaceutical Considerations for Rectal Drug Formulations. Frontiers in Pharmacology. 2019;10:1196. DOI: 10.3389/fphar.2019.01196
Purohit TJ, Hanning SM, Wu Z. Advances in rectal drug delivery systems. Pharmaceutical Development and Technology. 2018;23(10):942-52. DOI: 10.1080/10837450.2018.1484766
Lowry M. Rectal drug administration in adults: how, when, why. Nursing Times. 2016;112(8):12-4.
van Hoogdalem EJ, de Boer AG, Breimer DD. Pharmacokinetics of rectal drug administration, Part I. General considerations and clinical applications of centrally acting drugs. Clinical Pharmacokinetics. 1991;21(1):11-26. DOI: 10.2165/00003088-199121010-00002
Salem AE, Mohamed EA, Elghadban HM, Abdelghani GM. Potential combination topical therapy of anal fissure: development, evaluation, and clinical study†. Drug Delivery. 2018;25(1):1672-82. DOI: 10.1080/10717544.2018.1507059
Guideline on clinical development of fixed combination medicinal products (EMA/CHMP/158268/2017 Rev. 2). European Medicines Agency; 2017.
Guideline on equivalence studies for the demonstration of therapeutic equivalence for locally applied, locally acting products in the gastrointestinal tract† (CPMP/EWP/239/95 Rev. 1, Corr. 1). European Medicines Agency; 2018.
ICH Topic E 3. Structure and Content of Clinical Study Reports. Step 5. Note for guidance on structure and content of clinical study reports (CPMP/ICH/137/95). European Medicines Agency; 1996.
Guideline on the investigation of bioequivalence (CPMP/EWP/QWP/1401/98 Rev. 1/Corr). European Medicines Agency; 2010.
Teimouri A. Extemporaneously compounded topical calcium channel blockers for wounds and skin ulcers [MSc thesis]. Halifax, Nova Scotia: Dalhousie University; 2019.
Carapeti EA, Kamm MA, Evans BK, Phillips RKS. Topical diltiazem and bethanechol decrease anal sphincter pressure without side effects. Gut. 1999;45(5):719-22. DOI: 10.1136/gut.45.5.719
Cook TA, Branding AF, Mortensen NJ. The pharmacology of the internal anal sphincter and new treatments of ano-rectal disorders. Alimentary Pharmacology & Therapeutics. 2001;15(7):887-98. DOI: 10.1046/j.1365-2036.2001.00995.x
Chrysos E, Xynos E, Tzovaras G, Zoras OJ, Tsiaoussis J, Vassilakis SJ. Effect of nifedipine on rectoanal motility. Diseases of the Colon & Rectum. 1996;39(2):212-6. DOI: 10.1007/BF02068078
Antropoli C, Perrotti P, Rubino M, Martino A, De Stefano G, Migliore G, et al. Nifedipine for local use in conservative treatment of anal fissures: preliminary results of a multicenter study. Diseases of the Colon & Rectum. 1999;42(8):1011-5. DOI: 10.1007/BF02236693
Ezri T, Susmallian S. Topical nifedipine vs. topical glyceryl trinitrate for treatment of chronic anal fissure. Diseases of the Colon & Rectum. 2003;46(6):805-8. DOI: 10.1007/s10350-004-6660-8
Perrotti P, Antropoli M, Noschese G, Bartone G, De Stefano G, Pacifico F, et al. Topical Nifedipine®† for conservative treatment of acute haemorrhoidal thrombosis. Colorectal Disease. 2000;2(1):18-21. DOI: 10.1046/j.1463-1318.2000.00130.x
Gough MJ, Lewis A. The conservative treatment of fissure-in-ano. British Journal of Surgery. 1983;70(3):175-6. DOI: 10.1002/bjs.1800700312
Jonas M, Neal KR, Abercrombie JF, Scholefield JH. A randomized trial of oral vs. topical diltiazem for chronic anal fissures. Diseases of the Colon & Rectum. 2001;44(8):1074-8. DOI: 10.1007/BF02234624
Kujur ADS, Paul Ekka NM, Chandra S, Lal S, Malua S. Comparative Study to Assess the Effectiveness of Topical Nifedipine and Diltiazem in the Treatment of Chronic Anal Fissure. Journal of Family Medicine and Primary Care. 2020;9(11):5652-57. DOI: 10.4103/jfmpc.jfmpc_986_20
Neiger A, Herms E. [The symptomatic therapy of hemorrhoids and anal eczema - a report of experiences from proctology practice]. Schweizerische Rundschau für Medizin Praxis. 1990;79(31-32):918-20.
Cook TA, Brading AF, Mortensen NJ. Effects of nifedipine on anorectal smooth muscle in Vitro. Diseases of the Colon & Rectum. 1999;42(6):782-7. DOI: 10.1007/BF02236936
Cook TA, Brading AF, Mortensen NJ. Differences in contractile properties of anorectal smooth muscle and the effects of calcium channel blockade. British Journal of Surgery. 1999;86(1):70-5. DOI: 10.1046/j.1365-2168.1999.00998.x
Perrotti P, Bove A, Antropoli C, Molino D, Antropoli M, Balzano A, et al. Topical nifedipine with lidocaine ointment vs. active control for treatment of chronic anal fissure: results of a prospective, randomized, double-blind study. Diseases of the Colon & Rectum. 2002;45(11):1468-75. DOI: 10.1007/s10350-004-6452-1
Perrotti P, Antropoli C, Molino D, De Stefano G, Antropoli M. Conservative treatment of acute thrombosed external hemorrhoids with topical nifedipine. Diseases of the Colon & Rectum. 2001;44(3):405-9. DOI: 10.1007/BF02234741
Nelson RL, Manuel D, Gumienny C, Spencer B, Patel K, Schmitt K, et al. A systematic review and meta-analysis of the treatment of anal fissure. Techniques in Coloproctology. 2017;21(8):605-25. DOI: 10.1007/s10151-017-1664-2
Perrotti P, Dominici P, Grossi E, Antropoli C, Giannotti G, Cusato M, et al. Pharmacokinetics of anorectal nifedipine and lidocaine (lignocaine) ointment following haemorrhoidectomy: an open-label, single-dose, phase IV clinical study. Clinical Drug Investigation. 2009;29(4):243-56. DOI: 10.2165/00044011-200929040-00003
Perrotti P, Grumetto L, Barbato F, Antropoli C. Serum levels and possible haemodynamic effects following anorectal application of an ointment containing nifedipine and lignocaine: a study in healthy volunteers. Clinical Drug Investigation. 2006;26(8):459-67. DOI: 10.2165/00044011-200626080-00004
Raemsch KD, Sommer J. Pharmacokinetics and metabolism of nifedipine. Hypertension. 1983;5(4 pt 2):II18-24. DOI: 10.1161/01.hyp.5.4_pt_2.ii18
Traube M, Hongo M, McAllister Jr RG, McCallum RW. Correlation of plasma levels of nifedipine and cardiovascular effects after sublingual dosing in normal subjects. The Journal of Clinical Pharmacology. 1985;25(2):125-9. DOI: 10.1002/j.1552-4604.1985.tb02812.x
Kurosawa S, Kurosawa N, Owada E, Matsuhashi N, Ito K. Rectal administration of nifedipine: haemodynamic effects and pharmacokinetics in hypertensives. Journal of International Medical Research. 1987;15(3):121-7. DOI: 10.1177/030006058701500301
Kleinbloesem CH, Van Harten J, de Leede LGJ, van Brummelen P, Breimer DD. Nifedipine kinetics and dynamics during rectal infusion to steady state with an osmotic system. Clinical Pharmacology and Therapeutics. 1984;36(3):396-401. DOI: 10.1038/clpt.1984.194
Covino BG. Toxicity of local anesthetic agents. Acta Anaesthesiologica Belgica. 1988;39(3 suppl 2):159-64.
Tucker GT, Mather LE. Clinical pharmacokinetics of local anesthetics. Clinical Pharmacokinetics. 1979;4(4):241-78. DOI: 10.2165/00003088-197904040-00001
Echizen H, Eichelbaum M. Clinical Pharmacokinetics of Verapamil, Nifedipine and Diltiazem. Clinical Pharmacokinetics. 1986;11(6):425-49. DOI: 10.2165/00003088-198611060-00002
Covino BG. Pharmacology of local anesthetics. British Journal of Anaesthesia. 1986;58(7):701-16. DOI: 10.1093/bja/58.7.701
Tonsuwannont W, Praisontarangkul OA, Manorot M, Klangwarnwong D. Pharmacokinetics of oral lidocaine and nifedipine in patients with liver cirrhosis. Journal of the Medical Association of Thailand. 1996;79(5):309-19.
Hardman JG, Limbird LE, Molinoff PB, Ruddon RW, Gilman AG (editors). Goodman & Gilman's the pharmacological basis of therapeutics. 9th ed. New York: McGraw-Hill; 1996, 1905 p.
Shiau JM, Su HP, Chen HS, Hung KC, Lin SE, Tseng CC. Use of a topical anesthetic cream (EMLA) to reduce pain after hemorrhoidectomy. Regional Anesthesia and Pain Medicine. 2008;33(1):30-5. DOI: 10.1016/j.rapm.2007.07.012
Vickers ER, Marzbani N, Gerzina TM, McLean C, Punnia-Moorthy A, Mather L. Pharmacokinetics of EMLA cream 5% application to oral mucosa. Anesthesia Progress. 1997;44(1):32-7.
Leopold A, Wilson S, Weaver JS, Moursi AM. Pharmacokinetics of lidocaine delivered from a transmucosal patch in children. Anesthesia Progress. 2002;49(3):82-7.
Jensen SL. Treatment of first episodes of acute anal fissure: prospective randomised study of lignocaine ointment versus hydrocortisone ointment or warm sitz baths plus bran. British Medical Journal (Clinical Research Ed.). 1986;292(6529):1167-9. DOI: 10.1136/bmj.292.6529.1167
McDonald P, Driscoll AM, Nicholls RJ. The anal dilator in the conservative management of acute anal fissures. British Journal of Surgery. 1983;70(1):25-6. DOI: 10.1002/bjs.1800700109
Havlickova B, Weyandt GH. Therapeutic management of anal eczema: an evidence-based review. International Journal of Clinical Practice. 2014;68(11):1388-99. DOI: 10.1111/ijcp.12457
Brown AC, Sumfest JM, Rozwadowski JV. Histopathology of the internal anal sphincter in chronic anal fissure. Diseases of the Colon & Rectum. 1989;32(8):680-3. DOI: 10.1007/BF02555773
Benfeldt E, Serup J, Menné T. Effect of barrier perturbation on cutaneous salicylic acid penetration in human skin: in vivo pharmacokinetics using microdialysis and non-invasive quantification of barrier function. British Journal of Dermatology. 1999;140(4):739-48. DOI: 10.1046/j.1365-2133.1999.02859.x
Misra MC, Imlitemsu. Drug Treatment of Haemorrhoids. Drugs. 2005;65(11):1481-91. DOI: 10.2165/00003495-200565110-00003
Nisar PJ, Scholefield JH. Managing haemorrhoids. BMJ. 2003;327(7419):847-51. DOI: 10.1136/bmj.327.7419.847
Wynn T, Thompson C. Case report: wound care of a diabetic foot ulcer. International Journal of Pharmaceutical Compounding. 2004;8(4):265-7.
Santis AK, de Freitas ZMF, Ricci-Junior E, de Brito-Gitirana L, Fonseca LB, Santos EP. Nifedipine in semi-solid formulations for topical use in peripheral vascular disease: preparation, characterization, and permeation assay. Drug Development and Industrial Pharmacy. 2013;39(7):1098-106. DOI: 10.3109/03639045.2012.711833
Torsiello MJ, Kopacki MH. Transdermal nifedipine for wound healing: case reports. International Journal of Pharmaceutical Compounding. 2000;4(5):356-8.
Linares-Gil MJ, Valls J, Hereu-Boher P, Nebot FJ, De-Ramón B, Diaz-Munió E, et al. Topical Analgesia with Lidocaine Plus Diclofenac Decreases Pain in Benign Anorectal Surgery: Randomized, Doubleblind, and Controlled Clinical Trial. Clinical and Translational Gastroenterology. 2018;9(11):e210. DOI: 10.1038/s41424-018-0075-7
Phoenix™ Dry Heat Systems. Synersy.fr. Available from: http://www.synersy.fr/99310067-Rev.-04-18-Phoenix-Diffusion-Testing-Systems.pdf.
Thakker KD, Chern WH. Development and Validation of In Vitro Release Tests for Semisolid Dosage Forms-Case Study. Dissolution Technologies. 2003;10(2):10-5. DOI: 10.14227/DT100203P10
Validation of Analytical Procedures: Text and Methodology Q2(R1). Database.ich.org. Available from: https://database.ich.org/sites/default/files/Q2%28R1%29%20Guideline.pdf
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